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Vol. 12, No. 12, pp. 1812-1824, June 15, 1998
Department of Biological Chemistry and the Howard Hughes Medical
Institute, University of Michigan Medical Center, Ann Arbor,
Michigan 48109 USA
Eukaryotes respond to the presence of unfolded protein in the
endoplasmic reticulum (ER) by up-regulating the transcription of genes
encoding ER protein chaperones, such as BiP. We have isolated a novel
human cDNA encoding a homolog to Saccharomyces cerevisiae
Ire1p, a proximal sensor for this signal transduction pathway in yeast.
The gene product hIre1p is a type 1 transmembrane protein containing a
cytoplasmic domain that is highly conserved to the yeast counterpart
having a Ser/Thr protein kinase domain and a domain
homologous to RNase L. However, the luminal domain has extensively
diverged from the yeast gene product. hIre1p expressed in mammalian
cells displayed intrinsic autophosphorylation activity and an
endoribonuclease activity that cleaved the 5' splice site of yeast
HAC1 mRNA, a substrate for the endoribonuclease activity of
yeast Ire1p. Overexpressed hIre1p was localized to the ER with particular concentration around the nuclear envelope and some colocalization with the nuclear pore complex. Expression of Ire1p mRNA
was autoregulated through a process that required a functional hIre1p
kinase activity. Finally, overexpression of wild-type hIre1p constitutively activated a reporter gene under transcriptional control
of the rat BiP promoter, whereas expression of a catalytically inactive
hIre1p acted in a trans-dominant-negative manner to prevent transcriptional activation of the BiP promoter in response to ER stress
induced by inhibition of N-linked glycosylation. These results
demonstrate that hIre1p is an essential proximal sensor of the unfolded
protein response pathway in mammalian cells.
[Key Words: Unfolded protein response; signal transduction; RNA processing; nuclear pore comples; glucose deprivation; glucose regulated proteins; Ire1/Ern1]
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